The present invention provides a recombinant oncolytic Herpes Simplex Virus (oHSV) comprising a non-HSV ligand specific for a molecule (protein, lipid, or carbohydrate determinant) present on the surface of a cell (such as a cancer cell) and a plurality of copies of one or more microRNA target sequences inserted into one or more HSV gene loci, preferably one or more HSV gene(s) required for replication of HSV in normal (i.e., non-cancerous) cells, and a deletion of the internal repeat (joint) region in the HSV genome comprising one copy of the ICP0, ICP34.5, LAT, and ICP4 genes and the ICP47 promoter. The invention further provides stocks and pharmaceutical compositions comprising the inventive oHSV and methods for killing tumor cells employing the inventive oHSV.

The present invention relates to an oncolytic virus which is, or is derived from, a clinical isolate which has been selected by comparing the abilities of a panel of three or more clinical isolates of the same viral species to kill tumor cells of two or more tumor cell lines in vitro and selecting a clinical isolate which is capable of killing cells of two or more tumor cell lines more rapidly and/or at a lower dose in vitro than one or more of the other clinical isolates in the panel.

Provided herein are methods and compositions for treating cancer in an individual comprising administering to the individual an effective amount of at least one immune checkpoint inhibitor and a p53 and/or MDA-7 (IL24) gene therapy. Also provided herein are methods of enhancing anti-tumor efficacy by administering an extracellular matrix-degrading protein. Also provided herein are methods of enhancing anti-tumor efficacy by administering metronomic chemotherapy (for agents described above, 5FU+CTX+GM-CSF) in combination with a p53 and/or IL24 gene therapy.

The present invention relates to oncolytic virus comprising: (i) a GM-CSF-encoding gene; and (ii) an immune co-stimulatory pathway activating molecule or an immune co-stimulatory pathway activating molecule-encoding gene.

The present invention provides a recombinant oncolytic Herpes Simplex Virus (oHSV) comprising a non-HSV ligand specific for a molecule (protein, lipid, or carbohydrate determinant) present on the surface of a cell (such as a cancer cell) and one or more copies of one or more microRNA target sequences inserted into one or more HSV gene loci, preferably one or more HSV gene(s) required for replication of HSV in normal (i.e., non-cancerous) cells. The invention further provides stocks and pharmaceutical compositions comprising the inventive oHSV and methods for killing tumor cells employing the inventive oHSV.

The present invention provides a method of treating cancer, which comprises administering a therapeutically effective amount of an oncolytic virus, an inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway and a further antagonist of an immune co-inhibitory pathway or an agonist of an immune co-stimulatory pathway to a patient in need thereof.

The present invention relates to an oncolytic virus comprising: (i) a fusogenic protein-encoding gene; and (ii) an immune stimulatory molecule-encoding gene.

The present invention provides a recombinant herpes simplex virus (HSV), comprising (a) a mutation of the glycoprotein B (gB) at position 285 or 549, (b) a plurality of copies of one or more microRNA target sequences inserted into a locus of an HSV gene required for HSV replication, wherein said target sequence is the reverse complement of microRNA miR-124 and wherein said target sequence is present in the ICP4 gene, and (c) a transgene encoding a matrix metalloproteinase. The present invention also provides a method of killing a cancerous cell using a recombinant HSV according to the invention and a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a recombinant HSV according to the invention.

The invention provides a herpes simplex virus (HSV) vector that does not express toxic HSV genes in non-complementing cells and which comprises a genome comprising one or more transgenes, wherein the vector is capable of expression of a transgene for at least 28 days in non-complementing cells. The disclosed vectors include vectors having deletions in the genes ICP0, ICP4, TCP22, TCP27 and TCP47, or alternative inactivating mutations, or vectors which express one or more of these genes with modified kinetics. The invention also relates to viral stocks of the inventive vectors, compositions thereof suitable for use therapeutically or for in vitro applications, and methods relating thereto. In another aspect, the invention provides a complementing cell, in particular a U20S cell, engineered to express ICP4 and ICP27 when the cell is infected with HSV for the production of the inventive vector. Said cells are disclosed as naturally complementing ICP0.

The invention provides a method for ameliorating chronic pain signaling involving transient receptor potential cation channel subfamily V member 1 (TRPV1) by expressing PP1 in neurons. The invention also provides HSV vectors for expressing PP1 within neurons and compositions comprising such vectors.